Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

A mild, operationally convenient, and practical method for the synthesis of synthetically useful N-arylsulfonylimines from N-(arylsulfonyl)benzylamines using K2S2O8 in the presence of pyridine as a base is reported herein. In addition, a “one-pot” tandem synthesis of pharmaceutically relevant N-heterocycles by the reaction of N-arylsulfonylimines, generated in situ with ortho-substituted anilines is also reported. The key features of the protocol include the use of a green oxidant, a short reaction time (30 min), chromatography-free isolation, scalability, and economical, delivering N-arylsulfonylimines in excellent yields of up to 96%. While the oxidation of N-aryl(benzyl)amines to N-arylimines using K2S2O8 is reported to be problematic, the oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines using K2S2O8 has been achieved for the first time. The dual role of the sulfate radical anion (SO4·−), including hydrogen atom abstraction (HAT) and single electron transfer (SET), is proposed to be involved in the plausible reaction mechanism.


Introduction
Among various imine compounds [1], N-arylsulfonylimines are perhaps the most prominent due to their unique stability, defined reactivity, and versatility in organic synthesis [2]. Leveraging their electron-deficient nature, N-arylsulfonylimines are widely used in organic transformations including nucleophilic addition, cycloaddition, imino-aldol reaction, ene reactions, aza-Friedel-Crafts reactions, and C-H functionaliza-tions ( [3] and references therein), leading to the synthesis of diverse nitrogen heterocycles of pharmaceutical relevance [4]. The traditional synthetic method for the preparation of N-arylsulfonylimines, similar to the preparation of N-arylimines, is based on the condensation of aromatic aldehydes and sulfonamides (Scheme 1a) [3,[5][6][7][8]. Because of the poor nucleophilicity of sulfonamides, the condensation reactions generally require Scheme 1: Various synthetic approaches to N-arylsulfonylimines.
harsh reaction conditions involving the use of strong acids, elevated temperature, and metal catalysts. Other methods include a non-dehydrative reaction of aldehydes with isocyanate analogs ( [3] and references therein) (Scheme 1b) and an oxidative reaction of primary benzylic alcohols with sulfonamides or chloramine-T ( [3] and references therein), and although they are elegant, they use substrates that are not readily accessible or toxic in nature. To overcome these limitations, oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines, as opposed to the traditional methods, under mild and neutral reaction conditions has been reported, although limited to a few methods. However, these methods of oxidation involving the use of CrO 2 [9], PhI(OAc) 2 /I 2 [10], TEMPO [11], NHPI [12], and metal catalysts [13], suffer from serious limitations including the use of metal catalysts, high temperature, risk of explosive hazards, production of large waste, and often low yield (Scheme 1c). Thus, an environmentally benign method that could deliver N-arylsulfonylimines under mild reaction conditions is highly desirable.
Previously, we reported a tandem oxidative intramolecular cyclization of N-aryl(benzyl)amines, having an internal nucleophile substituted at the ortho-position in the aniline ring, to nitrogen heterocycles using potassium persulfate (K 2 S 2 O 8 ) as the exclusive reagent [14]. The mechanistic study revealed that an initial oxidation to an iminium ion could be the key intermediate in the intramolecular cyclization step. In sharp contrast, when N-aryl(benzyl)amines that do not have an ortho-substituted nucleophile in aniline ring were used as the substrates in this reaction, N-arylimines were not isolated. Rather, an amide, in some cases, was isolated via oxidation of the benzylic methylene to a carbonyl group [14]. In the quest of a new method for the synthesis of N-arylsulfonylimines, we questioned ourselves whether N-(arylsulfonyl)benzylamines would behave similarly as N-aryl(benzyl)amines under K 2 S 2 O 8 -mediated oxidative conditions and could provide a platform for the synthesis of N-arylsulfonylimines.
To this endeavor, we have developed a method for the synthesis of N-arylsulfonylimines from N-(arylsulfonyl)benzylamines using K 2 S 2 O 8 in the presence of pyridine as a base. The key findings include a) requirement of a mild base for the formation N-arylsulfonylimines, and b) stability of N-arylsulfonylimines, unlike N-arylimines, under the oxidative conditions. Further, to demonstrate the scope and applicability of this approach, a gram-scale synthesis and a "one-pot" tandem synthesis of pharmaceutically relevant N-heterocycles by the reaction of in situ-generated N-arylsulfonylimines with various orthosubstituted anilines were also developed. The mechanism of the oxidation is believed to occur via hydrogen atom abstraction (HAT) followed by single electron transfer (SET) enabled by the sulfate radical anion (SO 4 ·− ).

Results and Discussion
Initially, we investigated the reaction of N-benzenesulfonyl(benzyl)amine (1a) as a model substrate with K 2 S 2 O 8 in MeCN at 80 °C for 12 h, conditions that were used earlier in our previous study [14]. Unfortunately, no product formation was observed under these conditions, while substrate 1a remained unreacted (Table 1, entry 1). When the solvent was changed to H 2 O, a trace quantity of product formation was observed (Table 1, entry 2). To our surprise, when 2 equiv of pyridine were used as an additive along with the oxidant K 2 S 2 O 8 in MeCN, the desired product N-benzenesulfonylimine 2a was obtained in 90% yield (Table 1, entry 3). Subsequently, we carried out further optimization studies by changing the additive, solvent, temperature, and reaction time to obtain the best possible yield of the product 2a (Table 1). Interestingly, when duration of the reaction was reduced to 1 h, product 2a was obtained in 96% yield with complete conversion of substrate 1a ( using K 2 S 2 O 8 in the presence or absence of a base is unsuccessful, the oxidation of N-arylsulfonyl(benzyl)amines 1a to imines 2a was achieved under the optimized conditions. Distinctly, the use of a base is the key to success in this oxidation. Perhaps more importantly, the stability of N-benzenesulfonylimine 2a, unlike N-arylimines, under the oxidative conditions is noteworthy.
With the optimized reaction conditions in hand (Table 1,  Furthermore, when various other ortho-substituted aniline derivatives such as 2-aminobenzylamine, 2-aminothiophenol, and o-phenylenediamine are reacted with imine 2a in a similar manner, the corresponding N-heterocycles 4c-f were obtained in good to moderate yield. However, the reaction with 2-aminophenol did not give the corresponding cyclized product 4g. This could be possibly due to the poor nucleophilicity of the ortho-OH group in 2-aminophenol thereby restricting the intramolecular nucleophilic addition and as a result the corresponding cyclized product is not formed. The synthesis of these nitrogen heterocycles signifies the innate ability of in situ-generated N-arylsulfonylimines in a variety of reactions with various ortho-substituted anilines without the need for pre-isolation or purification. Next, in order to determine whether the reaction proceeds via a radical pathway, we performed a control experiment. When substrate 1a was treated with the radical scavenger TEMPO under the optimized reaction conditions, the formation of product 2a was completely suppressed (Scheme 4). This confirms that the reaction proceeds via a radical pathway.
Based on the literature [15,16], our previous experience [14,17,18], and current understanding, a plausible mechanism for the benzylic oxidation is depicted in Scheme 5. Initially, a sulfate radical anion (SO 4 ·− ) is generated by homolytic cleavage of the peroxy linkage under heating conditions [17]. The hydrogen atom is abstracted from the benzylic position of 1 by SO 4 ·− , generating benzylic radical 1aa [14][15][16]. A single electron transfer (SET) could subsequently occur from 1aa to form the reactive species 1ab. Finally, the base abstracts the activated Scheme 6: Plausible mechanism for one-pot synthesis of N-heterocycles.
NH proton to produce imine 2. The dual role of SO 4 ·− involving HAT and SET is proposed in this plausible mechanism, which requires further investigation. Similarly, a plausible mechanism for the one-pot synthesis of N-heterocycles is shown in Scheme 6. Initially, the N-arylsulfonylimine 2, generated in situ from the corresponding N-(arylsulfonyl)benzylamine 1, undergoes transimination with the ortho-substituted aniline 3 to form imine 3ab via 3aa. Subsequent intramolecular nucleophilic addition in imine 3ab produces intermediate 3ac, which upon oxidation delivers the desired N-heterocycle 4.

Conclusion
In conclusion, we have developed a complementary approach to the currently available methods for the oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines using K 2 S 2 O 8 and pyridine as a base. While N-arylimines are difficult to prepare by the oxidation of N-aryl(benzyl)amines using K 2 S 2 O 8 , N-arylsulfonylimines are successfully prepared and are quite stable under the oxidative conditions. In addition, we demonstrated a "one-pot" tandem synthesis of pharmaceutically relevant N-heterocycles through the reaction of in situ-generated N-arylsulfonylimines with ortho-substituted anilines. The key features including the use of a green oxidant, a short reaction time, chromatography-free isolation, and scalability mark a distinction from the contemporary methods. Although we propose a dual role for SO 4 ·− involving both hydrogen atom abstraction (HAT) and single electron transfer (SET), further investigation of the mechanism would enrich our understanding of persulfate-mediated oxidative reactions.

Supporting Information
Supporting Information File 1 General procedures, product characterization, and copies of 1 H NMR and 13 C NMR spectra of all compounds.